title: The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics.
abstract: The microtubule-associated protein tau, which becomes hyperphosphorylated and pathologically aggregates in a number of these diseases, is extremely sensitive to manipulations of chaperone signaling. For example, Hsp90 inhibitors can reduce the levels of tau in transgenic mouse models of tauopathy. Because of this, we hypothesized that a number of Hsp90 accessory proteins, termed co-chaperones, could also affect tau stability. Perhaps by identifying these co-chaperones, new therapeutics could be designed to specifically target these proteins and facilitate tau clearance. Here, we report that the co-chaperone Cdc37 can regulate aspects of tau pathogenesis. We found that suppression of Cdc37 destabilized tau, leading to its clearance, whereas Cdc37 overexpression preserved tau. Cdc37 was found to co-localize with tau in neuronal cells and to physically interact with tau from human brain. Moreover, Cdc37 levels significantly increased with age. Cdc37 knockdown altered the phosphorylation profile of tau, an effect that was due in part to reduced tau kinase stability, specifically Cdk5 and Akt. Conversely, GSK3β and Mark2 were unaffected by Cdc37 modulation. Cdc37 overexpression prevented whereas Cdc37 suppression potentiated tau clearance following Hsp90 inhibition. Thus, Cdc37 can regulate tau in two ways: by directly stabilizing it via Hsp90 and by regulating the stability of distinct tau kinases. We propose that changes in the neuronal levels or activity of Cdc37 could dramatically alter the kinome, leading to profound changes in the tau phosphorylation signature, altering its proteotoxicity and stability.
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33613, USA.
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Justin H
authors.initials: JH
authors.lastname: Trotter
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Lawson
authors.forename: Grant D
authors.initials: GD
authors.lastname: Vestal
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.forename: Amelia G
authors.initials: AG
authors.lastname: Johnson
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jones
authors.forename: Qingyou
authors.initials: Q
authors.lastname: Li
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D018833:Chaperonins / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018832:Molecular Chaperones / Q000737:chemistry; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D016875:tau Proteins / Q000737:chemistry*
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D016875:tau Proteins; D018833:Chaperonins